PROJECT SUMMARY/ABSTRACT Induction of broadly neutralizing antibodies (bnAbs) against HIV-1 is an utmost critical goal towards the development of a protective AIDS vaccine. In this R21 proposal, we will explore the feasibility of developing novel immunogens and evaluate its ability to prime antibody responses towards the neutralizing epitope targeted by a bnAb 10E8 on the membrane proximal external region (MPER) of HIV-1 gp41. 10E8 has been shown to neutralize ~98% of all HIV-1 isolates tested. Thus, our proposal to develop an immunogen that could lead to induction of 10E8-like bnAbs is highly significant. This proposal is based on the scientific premise that a priming immunogen (primogen) plays a critical role in generating a B-cell repertoire that will determine antibody responses during subsequent exposures to boosting immunogens. As such, developing a primogen that can induce antibodies directed predominantly against the 10E8 neutralizing epitope is of paramount importance. The major innovation and the focus of this proposal is HM6HB immunogen. It is comprised of a modified heptad repeat region 1 (HR1) and the MPER of gp41. It is predicted to form a stable six-helix bundle (6HB) structure. The primary objective of this proposal is to generate a lumazine synthase nanoparticle-based immunogen (HM6HB-LS) that could be used as a primogen to focus antibody responses towards the 10E8 neutralizing epitope. Successful completion of this study would overcome a critical roadblock towards development of a protective AIDS vaccine.